6-benzoxazinyl- and 6-benzothiazinyl 2,3,4,5-tetrahydropyridazin-3-ones

ABSTRACT

The synthesis of benzoxazinyl- and benzothiazinylpyridazinone compounds is described. The novel compounds are cardiotonic agents and inhibitors of phosphodiesterase. In addition, the compounds are useful as smooth muscle relaxants and bronchodilators.

This is a continuation of application Ser. No. 07/125,142 filed Dec. 2,1987 which is a continuation-in-part of application Ser. No. 64,638,filed June 22, 1987, now U.S. Pat. No. 7,766,118, which in turn is acontinuation-in-part of application Ser. No. 944,316, filed Dec. 22,1986, now U.S. Pat. No. 4,721,484.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to compounds of the formula: ##STR1## asfurther defined herein. The compounds are useful as cardiotonic andvasodilating agents and as inhibitors of phosphodiesterase fraction IIIand platelet aggregation. In addition, the compounds are active assmooth muscle relaxants and bronchodilators. The present inventionfurther relates to intermediates of these compounds as further definedherein.

2. Description of the Prior Art

Quinoline substituted pyridazin-3-ones have been shown to be cardiotonicagents and platelet aggregation inhibitors. Published European PatentApplication No. 155,798 and British Patent No. 2,031,404 describecompounds of the formula: ##STR2## where R₁, R₂ and R₃ may be H or loweralkyl.

U.S. Pat. No. 4,562,190 describes benzothiazole substitutedpyridazin-3-ones of the formula ##STR3## where R₁ is C₁ -C₆ alkyl and R₂is H, C₁ -C₆ alkyl or aryl.

SUMMARY OF THE INVENTION

The present invention is directed to 6-benzoxazinyl- and6-benzothiazinyl-2,3,4,5-tetrahydropyridazin-3-ones of the generalformula: ##STR4## where X may be H₂ or O;

Y may be O or S;

R₁ may be H, C₁₋₆ straight- or branched-chain alkyl or C₃₋₆ cycloalkyl;

R₂ may be H, C₁₋₆ straight- or branched-chain alkyl, C₃₋₆ cycloalkyl orC₂₋₆ alkenyl;

R₃ may be H, C₁₋₆ straight- or branched-chain alkyl or C₃₋₆ cycloalkyl,and when X is H₂, R₃ may also be C₂ -C₆ acyl, arylacyl such as benzoyland phenylacetyl, or alkanesulfonyl such as methanesulfonyl;

R₄ may be H, halogen, C₁₋₆ straight- or branched-chain alkyl or C₁₋₆alkoxy;

R₅ and R₆ may each be H, C₁₋₆ straight- or branched-chain alkyl or C₃₋₆cycloalkyl; and

the dotted line may be a single or double bond between C4 and C5 of thepyridazine ring.

The compounds of formula I are useful as cardiotonic agents having along duration of activity and are very potent inhibitors ofphosphodiesterase fraction III.

The present invention is further directed to intermediates of thecompounds of formula I having the general formulas of ##STR5## where R₁,R₃, R₄, R₅ and R₆ may independently be H, C₁₋₆ straight- orbranched-chain alkyl or C₃₋₆ cycloalkyl;

R₇ may be H, C₁₋₆ straight- or branched-chain alkyl, -CN or mono- ordi-C₁₋₆ alkyl amino;

X may be H₂ or O;

Y may be O or S;

R, W and Z may independently be H, C₁₋₆ straight- or branched-chainalkyl, C₂₋₆ acyl or --C(O)CHR₄ CH₂ C(O)OR₈ ; and

R₈ may be H or C₁₋₆ straight- or branched-chain alkyl.

In the intermediates of the general formula IV, when R₇ is --CN or mono-or di-C₁₋₆ alkyl amino, the intermediates may also include thequaternary ammonium salts thereof.

In the intermediates of the general formula V, R₃ may also be C₂₋₆ acyl,arylacyl or C₁₋₆ alkylsulfonyl when X is H₂. In addition, when one of R,W and Z is --C(O)CHR₄ CH₂ C(O)OR₈, then the others cannot be the samesubstituent.

DETAILED DESCRIPTION OF THE INVENTION

The invention in its broadest aspects relates to pyridazinone compoundswhich exhibit cardiotonic activity, vasodilating activity, plateletanti-aggregatory activity and phosphodiesterase fraction III inhibitoryactivity. The pyridazinone compounds of the invention demonstratingthese activities are shown by formula I above. The pyridazinonecompounds contain a benzoxazine ring. The invention further relates tointermediates of the pyridazinone compounds.

The preferred compounds of the present invention are those wherein R₁ isCH₃, R₂ and R₃ are hydrogen, R₄, R₅ and R₆ are H or CH₃, X is O or H₂and the pyridazinone ring is attached at C-7 of the benzoxazine ring.

The starting materials for preparing the compounds of the presentinvention can be prepared as shown in Scheme 1. ##STR6## wherein R'₃ isRCO or RSO₂, wherein R is lower alkyl and the alkyl group contains 1-6carbon atoms, and R₄, R₅ and R₆ are as previously defined.

The benzoxazinone or benzothiazine 2 is prepared from compound 1 by theprocedure of Shridhar, Org. Prep. Proc. Int. 14, 195 (1982). Compound 2is refluxed for several hours in one equivalent of diborane intetrahydrofuran to produce the benzoxazine or benzothiazine 3. Compound3, where R₃ is H, is treated with a sulfonyl or acyl compound such asmethanesulfonyl chloride or acetyl chloride and pyridine in a solventsuch as dichloromethane and refluxed for several hours to produce thebenzoxazine or benzothiazine 4.

The compounds of formula I can be prepared as shown in Schemes 2, 3 and4. ##STR7##

The benzoxazine or benzothiazine 2 or 4 is acylated by the method ofThyes, J. Med. Chem. 26, 800 (1983) using succinic anhydride to producethe compound 5. Compound 5 is refluxed for 1-8 hours with 2.2equivalents of hydrazine in an alcohol solvent such as methanol to givecompound 6. Alternatively, compound 6 can be prepared by firstesterifying compound 5 in alcoholic HCl to form compound 8 and thenreacting compound 8 with hydrazine. Compound 6 can be alkylated at the2-position of the pyridazinone ring by treatment in an inert solventsuch as dimethylformamide with an alkali metal base such as sodiumhydride and subsequent treatment with an alkyl halide, R₂ X wherein R₂is as defined above and X is chloro, bromo or iodo, at about 0°-40° C.for about 0.5-8 hours to give compound 7. Alternatively, compound 5(when R₃ is H) can be alkylated at the 4-position as described above togive compound 8. Compound 8 is refluxed with hydrazine to producecompound 6. The N-acylated derivative 7 (X=H₂ ; R₃ =acyl or sulfonyl)was prepared from 6 (X=H₂ ; R₃ =H) by treatment with a base, such astriethylamine, and the appropriate acid chloride, such as acetylchloride, methanesulfonyl chloride, benzoyl chloride, for example, asdescribed above. ##STR8##

To prepare a 5-alkylated pyridazinone, the benzoxazine or benzothiazine2 or 4 is acylated with propionyl chloride by the method of Thyes,supra, and the resulting product is converted to compound 9 by themethod of McEvoy and Allen, J. Org. Chem. 38, 4044 (1973). Compound 9 isreacted with hydrazine or alkylated as described above to producecompounds 10 and 11, respectively. Compound 11 can be reacted withhydrazine to give compound 10. Compound 10 can be alkylated at the2-position of the pyridazinone ring or acylated at the 4-position of thebenzoxazine or benzothiazine ring as described previously. ##STR9##

The benzoxazine or benzothiazine 2 or 4, when R₄ is ##STR10## at the7-position of the ring, is converted to compound 12 by the method ofMcEvoy and Allen, supra. Compound 12 is reacted with hydrazine oralkylated as described above to produce compounds 13 and 14,respectively. Compound 14 can be reacted with hydrazine to give compound13. Compound 13 can be alkylated at the 2-position of the pyridazinonering or acylated at the 4-position of the benzoxazine or benzothiazinering as previously described.

Pharmaceutical compositions containing a compound of the presentinvention as the active ingredient in intimate admixture with apharmaceutical carrier can be prepared according to conventionalpharmaceutical compounding techniques. The carrier may take a widevariety of forms depending on the form of preparation desired foradministration, e.g., intravenous, oral or parenteral. The compositionmay also be administered by means of an aerosol. In preparing thecompositions in oral dosage form, any of the usual pharmaceutical mediamay be employed, such as, for example, water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like in thecase of oral liquid preparations (such as, for example, suspensions,elixirs and solutions); or carriers such as starches, sugars, diluents,granulating agents, lubricants, binders, disintegrating agents and thelike in the case of oral solid preparations (such as, for example,powders, capsules and tablets). Because of their ease in administration,tablets and capsules represent the most advantageous oral dosage unitform, in which case solid pharmaceutical carriers are obviouslyemployed. If desired, tablets may be sugar-coated or enteric-coated bystandard techniques. For parenterals, the carrier will usually comprisesterile water, though other ingredients, for example, to aid solubilityor for preservative purposes, may be included, injectable suspensionsmay also be prepared, in which case appropriate liquid carriers,suspending agents and the like may be employed. The pharmaceuticalcompositions will generally contain dosage unit, e.g., tablet, capsule,powder, injection, teaspoonful and the like, from about 0.001 to about10 mg/kg, and preferably from about 0.01 to about 0.1 mg/kg of theactive ingredient.

The following examples describe the invention in greater particularityand are intended to be a way of illustrating but not limiting theinvention.

EXAMPLE 1 3,4-Dihydro-7-(1-oxopropyl)-3-oxo-1,4(2H)-benzoxazine

4-Amino-3-hydroxypropiophenone (32 g) was dissolved in 250 ml of methylisobutyl ketone and 250 ml of water containing 40 g of sodiumbicarbonate. Chloroacetyl chloride (17 ml) was added to the rapidlystirring mixture at 0° C. The mixture was then heated at reflux for fourhours. Upon cooling, the title compound was isolated by filtration andwashed with ether. Yield: 35 g (88%), mp 174.5°-176° C.

The following compounds were prepared by the above procedure, using theappropriate starting materials:

3,4-dihydro-3-oxo-1,4(2H)-benzoxazine, mp 170°-171° C.;

3,4-dihydro-6-methyl-3-oxo-1,4(2H)-benzoxazine, mp 204.5°-205.5° C.;

3,4-dihydro-7-methyl-3-oxo-1,4(2H)-benzoxazine, mp 193°-195° C.;

3,4-dihydro-2-methyl-3-oxo-1,4(2H)-benzoxazine, mp 143°-145° C.;

3,4-dihydro-2,2-dimethyl-3-oxo-1,4(2H)-benzoxazine, mp 161°-163° C.;

3,4-dihydro-2,7-dimethyl-3-oxo-1,4(2H)-benzoxazine, mp 152°-153° C.;

3,4-dihydro-4-(1-methylethyl)-3-oxo-1,4(2H)-benzoxazine, oil;

3,4-dihydro-4-cyclopentyl-3-oxo-1,4(2H)-benzoxazine, oil;

3,4-dihydro-2-methyl-4-(1-methylethyl)-3-oxo-1,4(2H)-benzoxazine, oil;

3,4-dihydro-2-methyl-4-cyclopentyl-3-oxo-1,4(2H)-benzoxazine, oil; and

3,4-dihydro-7-(1-oxoethyl)-3-oxo-1,4(2H)-benzoxazine, mp 193°-196° C.

The following compounds were prepared by the above procedure, using theappropriate starting materials:

3,4-dihydro-3-oxo-1,4[2H]benzothiazine;

3,4-dihydro-3-oxo-7-(1-oxopropyl)-1,4[2H]benzothiazine;

3,4-dihydro-2-methyl-3-oxo-1,4[2H]benzothiazine; and

3,4-dihydro-2,2-dimethyl-3-oxo-1,4[2H]benzothiazine.

EXAMPLE 2 3,4-Dihydro-1,4(2H)-benzoxazine

3,4-Dihydro-3-oxo-1,4(2H)-benzoxazine was refluxed for several hours inone equivalent of diborane in tetrahydrofuran. Excess sodium hydroxidesolution was added, the product was extracted with ether and the solventwas evaporated to give the title compound as an oil.

The following compounds were prepared by the above procedure, using theappropriate starting materials:

3,4-dihydro-6-methyl-1,4(2H)-benzoxazine and

3,4-dihydro-2-methyl-1,4(2H)-benzoxazine.

EXAMPLE 3 3,4-Dihydro-2,7-dimethyl-4-(1-oxoethyl)-1,4(2H)-benzoxazine

3,4-Dihydro-2,7-dimethyl-1,4(2H)-benzoxazine was dissolved indichloromethane, and one equivalent each of acetyl chloride andtriethylamine were added in that order. The mixture was refluxed forseveral hours, cooled and washed with water, and then with saturatedNaHCO₃ solution. Evaporation of the organic layer provided the product,mp 60.5°-63° C.

The following compounds were prepared by the above procedure, using theappropriate starting materials:

3,4-dihydro-4-methanesulfonyl-1,4(2H)-benzoxazine, mp 74.5°-77° C.;

3,4-dihydro-4-(1-oxoethyl)-1,4(2H)-benzoxazine, oil; and

3,4-dihydro-2-methyl-4-(1-oxoethyl)-1,4(2H)-benzoxazine, mp 80°-82° C.

EXAMPLE 44-Oxo-4-(3,4-dihydro-2-methyl-3-oxo-1,4(2H)-benzoxazin-6-yl)butyric acid

3,4-Dihydro-2-methyl-3-oxo-1,4(2H)-benzoxazine (11.4 g) and succinicanhydride (7 g) were added to 93 g of aluminum chloride and 15.3 ml ofdimethylformamide. The mixture was stirred at 70° C. for 2.5 hours andthen poured onto ice, giving a solid which was collected by filtrationand washed with water. Drying under vacuum gave 16.5 g of the titlecompound (90% yield), mp 198°-200° C.

The following compounds were prepared by the above procedure, using theappropriate starting materials:

4-oxo-4-(3,4-dihydro-3-oxo-1,4(2H)-benzoxazin-6-yl)butyric acid, mp206°-208° C.;

4-oxo-4-(3,4-dihydro-2,2-dimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)butyricacid;

4-oxo-4-(3,4-dihydro-7-methyl-3-oxo-1,4(2H)-benzoxazin-6-yl)butyricacid, mp 226°-228° C.;

4-oxo-4-(3,4-dihydro-2,7-dimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)butyricacid;

4-oxo-4-(3,4-dihydro-4-methanesulfonyl-1,4(2H)-benzoxazin-6-yl)butyricacid, mp 184°-187° C.;

4-oxo-4-(3,4-dihydro-4-(1-oxoethyl)-1,4(2H)-benzoxazin-6-yl)butyricacid, mp 143°-144.5° C.;

4-oxo-4-(3,4-dihydro-6-methyl-3-oxo-1,4(2H)-benzoxazin-8-yl)butyricacid; and

4-oxo-4-(3,4-dihydro-6-methyl-3-oxo-1,4(2H)-benzoxazin-7-yl)butyricacid.

EXAMPLE 5 Methyl4-oxo-4-(3,4-dihydro-4-methyl-3-oxo-1,4(2H)-benzoxazin-6-yl)butyrate

3,4-Dihydro-3-oxo-1,4(2H)-benzoxazine was alkylated by dissolving theacid in dimethylformamide and adding two equivalents of 60% sodiumhydride in oil suspension. After one-half hour, two equivalents ofmethyl iodide were added. The mixture was stirred under nitrogen for 12hours, then poured into water. The product was collected by extractioninto ethyl acetate and evaporation of the solvent, mp 139°-140° C.

The following compounds were prepared by the above procedure, using theappropriate starting materials:

methyl4-oxo-4-(3,4-dihydro-2,4dimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)butyrate,oil;

methyl4-oxo-4-(3,4-dihydro-4,7-dimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)butyrate,oil;

methyl4-oxo-4-(3,4-dihydro-2,4,7-trimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)butyrate,oil;

methyl4-oxo-4-(3,4-dihydro-4,6-dimethyl-3-oxo-1,4(2H)-benzoxazin-8-yl)butyrate,oil;

methyl4-oxo-4-(3,4-dihydro-4,6-dimethyl-3-oxo-1,4(2H)-benzoxazin-7-yl)butyrate,oil;

methyl4-oxo-4-(3,4-dihydro-2,4-trimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)butyrate,oil;

methyl4-oxo-4-(3,4-dihydro-4-methyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-3-methylbutyrate,oil;

methyl4-oxo-4-(3,4-dihydro-2,4-dimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-3-methylbutyrate,oil;

methyl4-oxo-4-(3,4-dihydro-4,7-dimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-3-methylbutyrate,oil;

methyl4-oxo-4-(3,4-dihydro-2,4,7-trimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-3-methylbutyrate,oil;

methyl4-oxo-4-(3,4-dihydro-4,6-dimethyl-3-oxo-1,4(2H)-benzoxazin-8-yl)-3-methylbutyrate,oil; and

methyl4-oxo-4-(3,4-dihydro-4-methyl-3-oxo-1,4(2H)-benzoxazin-7-yl)-3-methylbutyrate,oil.

EXAMPLE 64-Oxo-4-(3,4-dihydro-7-methyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-3-methylbutyricacid

A. 3,4-Dihydro-7-methyl-3-oxo-1,4(2H)-benzoxazine was acylated withpropionyl chloride by the method of Example 4 in 85% yield. The productof this operation was converted to the title compound as follows:

B. 3,4-Dihydro-7-methyl-6-(1-oxopropyl)-3-oxo-1,4(2H)-benzoxazine (23.7g) was added to a mixture of 13 g of dimethylamine hydrochloride and 15ml of 37% aqueous formaldehyde solution in 68 ml of acetic anhydride.After heating on a steam bath for three hours, 50 ml of acetone wasadded and heating was continued for 15 minutes. The solvents wereremoved by evaporation at reduced pressure and the residue was dissolvedin 1N HCl and washed with ethyl acetate. The aqueous layer was basifiedwith sodium hydroxide and the resultant crystals were collected byfiltration. This product was dissolved in 500 ml of acetone and 10 ml ofiodomethane were added. After heating at reflux overnight, the solidwhich formed was collected by filtration and washed with acetone. Theproduct was dissolved in 400 ml of 50% aqueous methanol and 18 g ofpotassium cyanide in 200 ml of water was added. After stirring overnightat room temperature, the solid was collected and washed with water. Thedamp filter cake was suspended in 500 ml of 6N HCl and heated at refluxfor 1.5 hours. Upon cooling a white precipitate formed which wascollected by filtration and washed with water to give 19.4 g (81% yield)of the title compound, mp 169.5°-172° C.

The following compounds were prepared by the above procedure, usingappropriate starting materials:

4-oxo-4-(3,4-dihydro-1,4(2H)-benzoxazin-6-yl)-3-methylbutyric acid;

4-oxo-4-(3,4-dihydro-2-methyl-1,4(2H)-benzoxazin-6-yl)-3-methylbutyricacid;

4-oxo-4-(3,4-dihydro-3-oxo-1,4(2H)-benzoxazin-6-yl)-3-methylbutyricacid;

4-oxo-4-(3,4-dihydro-2-methyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-3-methylbutyricacid;

4-oxo-4-(3,4-dihydro-2,7-dimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-3-methylbutyricacid;

4-oxo-4-(3,4-dihydro-4-(1-methylethyl)-2-methyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-3-methylbutyricacid;

4-oxo-4-(3,4-dihydro-4-cyclopentyl-2-methyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-3-methylbutyricacid;

4-oxo-4-(3,4-dihydro-6-methyl-3-oxo1,4(2H)-benzoxazin-8-yl)-3-methylbutyricacid; and

4-oxo-4-(3,4-dihydro-6-methyl-1,4(2H)-benzoxazin-8-yl)-3-methylbutyricacid.

EXAMPLE 74-Oxo-4-(3,4-dihydro-3-oxo-1,4(2H)-benzoxazin-7-yl)-3-methylbutyric acid

3,4-Dihydro-7-(1-oxopropyl)-3-oxo-1,4(2H)-benzoxazine (from Example 1)was converted to the title compound by the method of Example 6B.

EXAMPLE 86-(3,4-Dihydro-4-methanesulfonyl-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-one

Ethyl4-oxo-4-(3,4-dihydro-4-methanesulfonyl-1,4-(2H)-benzoxazin-6-yl)butyratewas suspended in methanol and 2.2 equivalents of hydrazine were added.The mixture was brought to reflux and stirred for 24 hours. Uponcooling, crystals of the desired product formed and were collected byfiltration. Recrystallization from ethanol gave pure title compound, mp245° C.

Theor. C₁₃ H₁₅ N₃ O₄ S: C, 50.47; H, 4.90; N, 13.59. Found: C, 50.46; H,4.85; N, 13.67.

When in the above procedure, ethyl4-oxo-4-(3,4-dihydro-4-methanesulfonyl-1,4(2H)-benzoxazin-6-yl)-3-ethylbutyrate;ethyl4-oxo-4-(3,4-dihydro-4-methanesulfonyl-1,4(2H)-benzoxazin-6-yl)-3-hexylbutyrate;or ethyl4-oxo-4-(3,4-dihydro-4-methanesulfonyl-1,4(2H)-benzoxazin-6-yl)-3-(1-methylethyl)butyrateis utilized as the starting material, the corresponding 5-ethyl-,5-hexyl- or -5-(1-methylethyl)-pyridazin-3-one derivative is obtained.

EXAMPLE 96-(3,4-Dihydro-4-methanesulfonyl-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydro-2-methylpyridazin-3-one

6-(3,4-Dihydro-4-methanesulfonyl-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-one(3 g) was suspended in 50 ml of dimethylformamide and one equivalent of60% sodium hydride in oil was added. When gas evolution ceased, oneequivalent of methyl iodide was added and the mixture allowed to standfor 1.5 hours followed by one hour at 40° C. The mixture was cooled andthen poured into 200 ml of ice water, giving a precipitate that wascollected by filtration, washed with water and recrystallized fromethanol. The material was further purified by chromatography on silicagel eluted with 1:1 EtOAc:Et₂ O yielding 0.97 g of the title product, mp162°-165° C.

Theor. C₁₄ H₁₇ N₃ O₄ S: C, 51.99; H, 5.31; N, 13.00. Found: C, 51.92; H,5.32; N, 12.96.

EXAMPLE 106-(3,4-Dihydro-4-methanesulfonyl-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydro-2-pentylpyridazin-3-one

6-(3,4-Dihydro-4-methanesulfonyl-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-onewas reacted with pentyl bromide in place of methyl iodide following theprocedure of Example 9. The title compound was recovered, yield 1.46 g,mp 138°-139° C.

Theor. C₁₈ H₂₅ N₃ O₄ S: C, 56.96; H, 6.65; N, 11.07. Found: C, 56.67; H,6.49; N, 11.05.

When in the above procedure, bromocyclohexane or 2-bromopropane isutilized in place of pentyl bromide, the corresponding 2-cyclohexyl or2-(1-methylethyl)pyridazinone is obtained.

EXAMPLE 116-(3,4-Dihydro-4-methanesulfonyl-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydro-2-(2-propenyl)pyridazin-3-one

6-(3,4-Dihydro-4-methanesulfonyl-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-onewas reacted with allyl bromide instead of methyl iodide, following theprocedure of Example 9. The title compound was recovered, yield 2.03 g,mp 153°-155° C.

Theor. C₁₆ H₁₉ N₃ O₄ S: C, 54.99; H, 5.49; N, 12.03. Found: C, 54.94; H,5.58; N, 11.92.

EXAMPLE 126-(3,4-Dihydro-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-one

The method of Example 8 was followed using4-oxo-4-(3,4-dihydro-1,4-(2H)-benzoxazin-6-yl)butyric acid as thestarting material to give the title compound in 60% yield, mp 198°-199°C.

Theor. C₁₂ H₁₃ N₃ O₂ : C, 62.31; H, 5.68; N, 18.17. Found: C, 62.35; H,5.72; N, 18.18.

EXAMPLE 136-(4-Acetyl-3,4-dihydro-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-one

The method of Example 8 was followed using4-oxo-4-(3,4-dihydro-3,4-acetyl-1,4-(2H)-benzoxazin-6-yl)butyric acid asthe starting material to yield the title compound in 40% yield, mp156°-158° C.

Theor. C₁₄ H₁₅ N₃ O₃ : C, 61.52; H, 5.54; N, 15.38. Found: C, 61.49; H,5.55; N, 15.24.

EXAMPLE 146-(3,4-Dihydro-4-(3,4-dimethoxyphenylcarbonyl)-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-one

6-(3,4-Dihydro-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-onewas dissolved in methylene chloride and 1.1 equivalent of triethylamine.1.1 equivalent of 3,4-dimethoxybenzoylchloride was added and the mixtureheated at reflux for four hours. The solution was washed with sodiumbicarbonate solution and then evaporated to dryness. The residue waschromatographed on silica gel eluting with 1:1 ethyl acetate:ethylether. The title compound was collected as white needles, mp 207°-208°C.

Theor. C₂₁ H₂₁ N₃ O₅ : C, 63.78; H, 5.36; N, 10.63. Found: C, 63.78; H,5.40; N, 10.64.

EXAMPLE 156-(3,4-Dihydro-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one

The method of Example 8 was followed using4-oxo-4-(3,4-dihydro-1,4(2H)-benzoxazin-6-yl)-3-methylbutyric acid asthe starting material to produce the title compound, mp 166°-168° C.

Theor. C₁₃ H₁₅ N₃ O₂ : C, 63.65; H, 6.18; N, 17.13. Found: C, 63.47; H,6.22; N, 16.90.

When in the above procedure,4-oxo-4-(3,4-dihydro-1,4(2H)-benzoxazin-6-yl)-3-ethylbutyric acid;4-oxo-4-(3,4-dihydro-1,4(2H)-benzoxazin-6-yl)-3-hexylbutyric acid or4-oxo-4-(3,4-dihydro-1,4(2H)-benzoxazin-6-yl)-3-(1-methylethyl)butyricacid is utilized, the corresponding 5-ethyl-, 5-hexyl- or-5-(1-methylethyl)-pyridazin-3-one derivative is obtained.

EXAMPLE 166-(4-Acetyl-3,4-dihydro-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one

6-(3,4-Dihydro-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-onewas suspended in tetrahydrofuran and one equivalent of acetyl chloridewas added. After one half hour at 0° C., the solvent was removed invacuo, and the product was crystallized from ethanol in 61% yield, mp185.5°-186° C.

Theor. C₁₅ H₁₇ N₃ O₃ : C, 62.69; H, 5.97; N, 14.63. Found: C, 62.85; H,6.03; N, 14.64.

EXAMPLE 176-(3,4-Dihydro-4-methanesulfonyl-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one

The method of Example 16 was followed using methanesulfonyl chlorideinstead of acetyl chloride. Pyridine was added to the mixture. After onehour at 0° C., the mixture was warmed to room temperature and allowed tostir for 48 hours and then refluxed for 24 hours. Acetonitrile was addedand the mixture was adsorbed onto silica gel and eluted with ethylacetate. The title compound was crystallized from ethanol to give a 25%yield, mp 207°-212° C.

Theor. C₁₄ H₁₇ N₃ O₄ S: C, 51.99; H, 5.31; N, 13.00. Found: C, 52.42; H,5.31; N, 13.39.

EXAMPLE 186-(3,4-Dihydro-2-methyl-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-one

The method of Example 8 was followed using4-oxo-4-(3,4-dihydro-2-methyl-1,4(2H)benzoxazin-6-yl)butyric acid as thestarting material to give the desired product in 10% yield, mp294.5°-295.5° C.

Theor. C₁₃ H₁₅ N₃ O₂ : C, 63.65; H, 6.18; N, 17.13. Found: C, 63.37; H,6.16; N, 17.41.

When in the above procedure,4-oxo-4-(3,4-dihydro-2-methyl-7-pentyl-1,4(2H)-benzoxazin-6-yl)butyricacid;4-oxo-4-(3,4-dihydro-2-hexyl-7-isopropyl-1,4(2H)-benzoxazin-6-yl)-2-hexylbutyricacid;4-oxo-4-(3,4-dihydro-2-methyl-7-cyclohexyl-1,4(2H)-benzoxazin-6-yl)butyricacid;4-oxo-4-(3,4-dihydro-2-isobutyl-7-methoxy-1,4(2H)-benzoxazin-6-yl)butyricacid or4-oxo-4-(3,4-dihydro-2-cyclopentyl-1,4(2H)-benzoxazin-6-yl)butyric acidis used, the corresponding pyridazinone derivative is obtained.

EXAMPLE 196-(3,4-Dihydro-2-methyl-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one

The method of Example 8 was followed using4-oxo-4-(3,4-dihydro-2-methyl-1,4(2H)benzoxazin-6-yl)-3-methylbutyricacid as the starting material. The product was further purified bychromatography on silica gel, mp 179°-182° C.

Theor. C₁₄ H₁₇ N₃ O₂ : C, 64.83; H, 6.62; N, 16.21. Found: C, 64.51; H,6.64; N, 15.84.

When in the above procedure,4-oxo-4-(3,4-dihydro-2-methyl-1,4(2H)-benzoxazin-6-yl)-3-ethylbutyricacid;4-oxo-4-(3,4-dihydro-2-methyl-1,4(2H)benzoxazin-6-yl)-3-hexylbutyricacid or4-oxo-4-(3,4-dihydro-2-methyl-1,4(2H)benzoxazin-6-yl)-3-(1-methylethyl)butyricacid is utilized, the corresponding 5-ethyl-, 5-hexyl- or-5-(1-methylethyl)-pyridizin-3-one derivative is obtained.

EXAMPLE 206-(3,4-Dihydro-3-oxo-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-one

Following the method of Example 8, but using methyl4-oxo-4-(3,4-dihydro-3-oxo-1,4(2H)benzoxazin-6-yl)butyrate, the titlecompound was obtained and was recrystallized from ethanol and then fromacetonitrile as a hydrate, mp 274°-275° C.

Theor. C₁₂ H₁₁ N₃ O₃.H₂ O: C, 57.70; H, 4.65; N, 16.83. Found: C, 57.54;H, 4.50; N, 16.79.

EXAMPLE 216-(3,4-Dihydro-4-methyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-one

The method of Example 8 was followed using methyl4-oxo-4-(3,4-dihydro-4-methyl-3-oxo-1,4(2H)benzoxazin-6-yl)butyrate asthe starting material. The product was purified by column chromatographyfollowed by several recrystallizations from acetonitrile, mp 247°-247.5°C.

Theor. C₁₃ H₁₃ N₃ O₃ : C, 60.21; H, 5.06; N, 16.21. Found: C, 59.85; H,4.98; N, 16.26.

EXAMPLE 226-(3,4-Dihydro-3-oxo-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one

The method of Example 8 was followed using methyl4-oxo-4-(3,4-dihydro-3-oxo-1,4(2H)benzoxazin-6-yl)-3-methylbutyrate asthe starting material. The product was purified by crystallization fromacetonitrile, followed by column chromatography on silica gel and elutedwith 5% methanol in dichloromethane, mp 265°-267° C.

Theor. C₁₃ H₁₃ N₃ O₃. 1/4 H₂ O: C, 59.19; H, 5.17; N, 15.93. Found: C,59.22; H, 4.98; N, 15.92.

When in the above procedure,4-oxo-4-(3,4-dihydro-3-oxo-1,4(2H)-benzoxazin-6-yl)-3-ethylbutyrate;4-oxo-4-(3,4-dihydro-3-oxo-1,4(2H)-benzoxazin-6-yl)-3-hexylbutyrate or4-oxo-4-(3,4-dihydro-3-oxo-1,4(2H)benzoxazin-6-yl)-3-(1-methylethyl)butyrateis utilized, the corresponding 5-ethyl-, 5-hexyl- or-5-(1-methylethyl)-pyridazin-3-one derivative is obtained.

EXAMPLE 236-(3,4-Dihydro-4-methyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one

The method of Example 8 was followed using methyl4-oxo-4-(3,4-dihydro-4-methyl-3-oxo-1,4(2H)benzoxazin-6-yl)-3-methylbutyrateas the starting material. The product was purified by chromatography andeluted with 5% methanol in dichloromethane, mp 215°-218° C.

Theor. C₁₄ H₁₄ N₃ O₃ : C, 61.52; H, 5.54; N, 15.34. Found: C, 61.80; H,5.75; N, 15.63.

EXAMPLE 246-(3,4-Dihydro-2-methyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-one

The method of Example 8 was followed using4-oxo-4-(3,4-dihydro-2-methyl-3-oxo-1,4(2H)-benzoxazin-6-yl)butyric acidas the starting material, to produce the title compound in 75% yield, mp275°-276° C.

Theor. C₁₃ H₁₃ N₃ O₃ : C, 60.21; H, 5.06; N, 16.21. Found: C, 60.02; H,5.22; N, 16.08.

EXAMPLE 256-(3,4-Dihydro-2,4-dimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-one

The title compound was produced in 25% yield, by following the method ofExample 8, usingmethyl-4-oxo-4-(3,4-dihydro-2,4-dimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)butyrateas the starting material, mp 210°-211° C.

Theor. C₁₄ H₁₅ N₃ O₃.1/2 H₂ O: C, 59.56; H, 5.72; N, 15.16. Found: C,59.93; H, 5.48; N, 15.16.

EXAMPLE 266-(3,4-Dihydro-2-methyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one

The method of Example 8 was followed using4-oxo-4-(3,4-dihydro-2-methyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-3-methylbutyricacid as the starting material, to yield the title compound in 50% yield,mp 271°-272° C.

Theor. C₁₄ H₁₅ N₃ O₃ : C, 61.52; H, 5.54; N, 15.38. Found: C, 61.34; H,5.59; N, 15.41.

When in the above procedure,4-oxo-4-(3,4-dihydro-2-methyl-7-pentyl-3-oxo-1,4(2H)-benzoxazin-6-yl)butyricacid;4-oxo-4-(3,4-dihydro-2-hexyl-7-isopropyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-butyricacid;4-oxo-4-(3,4-dihydro-2-methyl-7-cyclohexyl-3-oxo-1,4(2H)-benzoxazin-6-yl)butyricacid;4-oxo-4-(3,4-dihydro-2-isobutyl-7-methoxy-1,4(2H)-benzoxazin-6-yl)butyricacid or4-oxo-4-(3,4-dihydro-2-cyclopentyl-3-oxo-1,4(2H)-benzoxazin-6-yl)butyricacid is used, the corresponding pyridazinone derivative is obtained.

EXAMPLE 276-(3,4-Dihydro-2,4-dimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one

Following the method of Example 8, using methyl4-oxo-4-(3,4-dihydro-2,4-dimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-3-methylbutyrateas the starting material, the title compound was obtained, in 40% yield,mp 184°-185° C.

Theor. C₁₅ H₁₇ N₃ O₃ : C, 62.70; H, 5.98; N, 14.63. Found: C, 62.75; H,5.95; N, 14.79.

EXAMPLE 286-(3,4-Dihydro-7-methyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-one

The method of Example 8 was followed, using4-oxo-4-(3,4-dihydro-7-methyl-3-oxo-1,4(2H)-benzoxazin-6-yl)butyric acidas the starting material, to produce the title compound in 55% yield, mp255°-257° C.

Theor. C₁₃ H₁₃ N₃ O₃ : C, 60.21; H, 5.06; N, 16.21. Found: C, 59.90; H,5.26; N, 15.95.

When in the above procedure,4-oxo-4-(3,4-dihydro-7-pentyl-3-oxo-1,4(2H)-benzoxazin-6-yl)butyricacid;4-oxo-4-(3,4-dihydro-2-hexyl-7-isopropyl-3-oxo-1,4(2H)-benzoxazin-6-yl)butyricacid;4-oxo-4-(3,4-dihydro-7-cyclohexyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-butyricacid;4-oxo-4-(3,4-dihydro-2-isobutyl-7-methoxy-3-oxo-1,4(2H)benzoxazin-6-yl)butyricacid or4-oxo-4-(3,4-dihydro-2-cyclopentyl-3-oxo-1,4(2H)-benzoxazin-6-yl)butyricacid is used, the corresponding pyridazinone derivative is obtained.

EXAMPLE 296-(3,4-Dihydro-4,7-dimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-one

The title compound was obtained, in 47% yield, by following the methodof Example 8, using methyl4-oxo-4-(3,4-dihydro-4,7-dimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)butyrateas the starting material, mp 227°-228.5° C.

Theor. C₁₄ H₁₅ N₃ O₃ : C, 61.52; H, 5.54; N, 15.38. Found: C, 61.65; H,5.57; N, 15.26.

EXAMPLE 306-(3,4-Dihydro-7-methyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one

The method of Example 8 was followed, using4-oxo-4-(3,4-dihydro-7-methyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-3-methylbutyricacid as the starting material, to give the title compound in 51% yield,mp 163°-166° C.

Theor. C₁₄ H₁₅ N₃ O₃.1/4 H₂ O: C, 60.52; H, 5.63; N, 15.13. Found: C,60.65; H, 5.62; N, 15.03.

EXAMPLE 316-(3,4-Dihydro-4,7-dimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one

Following the method of Example 8, using4-oxo-4-(3,4-dihydro-4,7-dimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-3-methylbutyrateas the starting material, the title compound was produced, mp 180°-182°C.

Theor. C₁₅ H₁₇ N₃ O₃ : C, 62.70; H, 5.98; N, 14.63. Found: C, 62.77; H,6.06; N, 14.57.

EXAMPLE 326-(3,4-Dihydro-2,7-dimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-one

The method of Example 8 was followed, using4-oxo-4-(3,4-dihydro-2,7-dimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)butyricacid to give the title compound, mp 252°-254° C.

Theor. C₁₄ H₁₅ N₃ O₃.1/4 H₂ O: C, 60.52; H, 5.64; N, 15.13. Found: C,60.50; H, 5.45; N, 15.63.

EXAMPLE 336-(3,4-Dihydro-2,4,7-trimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-one

Following the method of Example 8, using methyl4-oxo-4-(3,4-dihydro-2,4,7-trimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)butyrateas the starting material, the title compound was obtained, mp 210°-212°C.

Theor. C₁₅ H₁₇ N₃ O₃ : C, 62.70; H, 5.98; N, 14.63. Found: C, 62.85; H,6.11; N, 14.93.

EXAMPLE 346-(3,4-Dihydro-2,7-dimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one

The method of Example 8 was followed, using4-oxo-4-(3,4-dihydro-2,7-dimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-3-methylbutyricacid, to yield the title compound, mp 190°-191° C.

Theor. C₁₅ H₁₇ N₃ O₃.1/2 H₂ O: C, 60.80; H, 6.14; N, 14.18. Found: C,61.18; H, 6.42; N, 13.78.

EXAMPLE 356-(3,4-Dihydro-2,4,7-trimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one

Following the method of Example 8, using methyl4-oxo-4-(3,4-dihydro-2,4,7-trimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-3-methylbutyrateas the starting material, the title compound was produced, mp 190°-192°C.

Theor. C₁₆ H₁₉ N₃ O₃.1/2 H₂ O: C, 61.91; H, 6.51; N, 13.54. Found: C,62.02; H, 6.52; N, 13.86.

When in the above procedure,4-oxo-4-(3,4-dihydro-2,4-dimethyl-7-pentyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-3-methylbutyrate;4-oxo-4-(3,4-dihydro-2-hexyl-4-methyl-7-isopropyl-3-oxo-1,4-(2H)-benzoxazin-6-yl)-3-methylbutyrate;4-oxo-(3,4-dihydro-2,4-dimethyl-7-cyclohexyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-3-methylbutyrate;4-oxo-4-(3,4-dihydro-2-isobutyl-4-methyl-7-methoxy-3-oxo-1,4(2H)benzoxazin-6-yl)-3-methylbutyrate;or4-oxo-4-(3,4-dihydro-2-cyclopentyl-4,7-dimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-3-methylbutyrateis used, the corresponding pyridazinone derivative is obtained.

EXAMPLE 366-(3,4-Dihydro-2-methyl-4-(1-methylethyl)-3-oxo-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one

The method of Example 8 was followed, using4-oxo-4-(3,4-dihydro-4-(1-methylethyl)-3-oxo-1,4(2H)-benzoxazin-6-yl)-3-methylbutyricacid as the starting material to give the title compound, mp 204°-205°C.

Theor. C₁₇ H₂₁ N₃ O₃ : C, 64.73; H, 6.72; N, 13.33. Found: C, 64.67; H,6.66; N, 13.42.

EXAMPLE 376-(3,4-Dihydro-4-cyclopentyl-2-methyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one

Following the method of Example 8, using4-oxo-4-(3,4-dihydro-4-cyclopentyl-2-methyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-3-methylbutyricacid as the starting material, the title compound was obtained, mp220°-223° C.

Theor. C₁₉ H₂₃ N₃ O₃ : C, 66.84; H, 6.80; N, 12.31. Found: C, 64.61; H,6.78; N, 12.29.

EXAMPLE 386-(3,4-Dihydro-6-methyl-3-oxo-1,4(2H)-benzoxazin-8-yl)-2,3,4,5-tetrahydropyridazin-3-one

The method of Example 8 was followed, using4-oxo-4-(3,4-dihydro-6-methyl-3-oxo-1,4(2H)-benzoxazin-8-yl)butyric acidas the starting material to give the title compound, mp 266°-270° C.

Theor. C₁₃ H₁₃ N₃ O₃ : C, 60.21; H, 5.06; N, 16.21. Found: C, 60.13; H,5.26; N, 16.28.

EXAMPLE 396-(3,4-Dihydro-4,6-dimethyl-3-oxo-1,4(2H)-benzoxazin-8-yl)-2,3,4,5-tetrahydropyridazin-3-one

Following the method of Example 8, using4-oxo-4-(3,4-dihydro-4,6-dimethyl-3-oxo-1,4(2H)-benzoxazin-8-yl)butyrateas the starting material, the title compound was obtained in 16% yield,mp 266°-270° C.

Theor. C₁₄ H₁₅ N₃ O₃ : C, 61.52; H, 5.54; N, 15.38. Found: C, 61.18; H,5.64; N, 15.36.

EXAMPLE 406-(3,4-Dihydro-6-methyl-3-oxo-1,4(2H)-benzoxazin-8-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one

The method of Example 8 was followed, using4-oxo-4-(3,4-dihydro-6-methyl-3-oxo-1,4(2H)-benzoxazin-8-yl)butyric acidas the starting material, to give the title compound in 31% yield, mp252°-253.5° C.

Theor. C₁₄ H₁₅ N₃ O₃ : C, 61.52; H, 5.54; N, 15.38. Found: C, 61.11; H,5.68; N, 15.26.

EXAMPLE 416-(3,4-Dihydro-4,6-dimethyl-3-oxo-1,4(2H)-benzoxazin-8-yl)-2,3,4,5-tetrahydro-5-methylpyridan-3-one

The method of Example 8 was followed, using methyl4-oxo-4-(3,4-dihydro-4,6-dimethyl-3-oxo-1,4(2H)-benzoxazin-8-yl)-3-methylbutyrateas the starting material, to produce the title compound in 15% yieldafter column chromatography on silica gel eluted with 5% methanol indichloromethane, mp 212°-213° C.

Theor. C₁₅ H₁₇ N₃ O₃ : C, 62.69; H, 5.98; N, 14.63. Found: C, 62.27; H,5.92; N, 14.57.

EXAMPLE 426-(3,4-Dihydro-6-methyl-1,4(2H)-benzoxazin-8-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one

Following the method of Example 8, using ethyl4-oxo-4-(3,4-dihydro-6-methyl-1,4(2H)-benzoxazin-8-yl)-3-methylbutyrateas the starting material, the title compound was prepared in 60% yield,mp 160°-162° C.

Theor. C₁₄ H₁₇ N₃ O₃ : C, 64.83; H, 6.62; N, 16.21. Found: C, 64.87; H,6.66; N, 16.31.

When in the above procedure,4-oxo-4-(3,4-dihydro-6-methyl-1,4(2H)-benzoxazin-8-yl)-3-ethylbutyrate;4-oxo-4-(3,4-dihydro-6-methyl-1,4(2H)-benzoxazin-8-yl)-3-hexylbutyrateor4-oxo-4-(3,4-dihydro-6-methyl-1,4(2H)-benzosazin-8-yl)-3-(1-methylethyl)butyrateis utilized, the corresponding 5-ethyl-, 5-hexyl- or-5-(1-methylethyl)-pyridazin-3-one derivative is obtained.

EXAMPLE 436-(3,4-Dihydro-4,6-dimethyl-3-oxo-1,4(2H)-benzoxazin-7-yl)-2,3,4,5-tetrahydropyridazin-3-one

The method of Example 8 was followed, using methyl4-oxo-4-(3,4-dihydro-4,6-dimethyl-3-oxo-1,4(2H)-benzoxazin-7-yl)butyrateas the starting material to produce the title compound, mp 211°-213° C.

Theor. C₁₄ H₁₅ N₃ O₃ : C, 61.52; H, 5.54; N, 15.38. Found: C, 61.57; H,5.49; N, 15.28.

EXAMPLE 446-(3,4-Dihydro-2,2-dimethyl-3-oxo-1,4(2H)-benzoxazin-6yl)-2,3,4,5-tetrahydropyridazin-3-one

The method of Example 8 was followed, using4-oxo-4-(3,4-dihydro-2,2-dimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)butyricacid as the starting material, to give the title compound, mp 251°-254°C.

Theor. C₁₄ H₁₅ N₃ O₃ : C, 61.52; H, 5.54; N, 15.38. Found: C, 61.40; H,5.58; N, 15.74.

EXAMPLE 456-(3,4-Dihydro-2,2,4-trimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-one

Following the method of Example 8, using methyl4-oxo-4-(3,4-dihydro-2,2,4-trimethyl-3-oxo-1,4(2H)-benzoxazin-6-yl)butyrate,the title compound was produced, mp 169°-171° C.

Theor. C₁₅ H₁₇ N₃ O₃ C, 62.69; H, 5.98; N, 14.63. Found: C, 62.79; H,5.86; N, 14.40.

EXAMPLE 466-(3,4-Dihydro-3-oxo-1,4(2H)-benzoxazin-7-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one

The method of Example 8 was followed, using4-oxo-4-(3,4-dihydro-3-oxo-1,4(2H)-benzoxazin-7-yl)-3-methylbutyric acidas the starting material. The title compound was obtained andrecrystallized from dimethylformamide-water, then ethanol, mp >300° C.

Theor. C₁₃ H₁₃ N₃ O₃.1/4H₂ O: C, 59.18; H, 5.17; N, 15.93. Found: C,58.88; H, 5.04; N, 16.03.

When in the above procedure,4-oxo-4-(3,4-dihydro-3-oxo-1,4(2H)-benzoxazin-7-yl-3-ethylbutyrate;4-oxo-4-(3,4-dihydro-3-oxo-1,4(2H)-benzoxazin-7-yl)-3-hexylbutyrate or4-oxo-4-(3,4-dihydro-3-oxo-1,4(2H)-benzoxazin-7-yl)-3-(1-methylethyl)butyrateis utilized, the corresponding 5-ethyl-, 5-hexyl- or-5-(1-methylethyl)-pyridazin-3-one derivative is obtained.

EXAMPLE 476-(3,4-Dihydro-4-methyl-3-oxo-1,4(2H)-benzoxazin-7-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one

The method of Example 8 was followed, using methyl4-oxo-4-(3,4-dihydro-4-methyl-3-oxo-1,4(2H)-benzoxazin-7-yl)-3-methylbutyrate.The product was purified by chromatography on silica gel eluted with 5%CH₃ OH in CH₂ Cl₂, mp 188°-190° C.

Theor. C₁₄ H₁₅ N₃ O₃ : C, 61.52; H, 5.54; N, 15.38. Found: C, 61.45; H,5.68; N, 15.15.

EXAMPLE 486-(3,4-Dihydro-2-methyl-3-oxo-1,4(2H)-benzoxazin-7-yl)-2,3,4,5-tetrahydropyridazin-3-one

The method of Example 8 was followed, using4-oxo-4-(3,4-dihydro-2-methyl-3-oxo-1,4(2H)-benzoxazin-7-yl)butyricacid. The product was purified by column chromatography on silica geleluted with 5% CH₃ OH in CH₂ Cl₂. Trituration with water gave theproduct as a hydrate, mp 294°-295° C.

Theor. C₁₃ H₁₃ N₃ O₃.1/4H₂ O: C, 59.18; H, 5.15; N, 15.93. Found: C,59.15; H, 4.93; N, 15.83.

The corresponding 2-alkyl-pyridazinone derivatives of the compoundsprepared in any of the preceding examples are prepared in accordancewith the procedures of Examples 9 and 10. The corresponding 4-acyl,4-arylacyl or 4-alkane sulfonylbenzoxazinyl derivatives of the compoundsprepared in the preceding examples where R₃ =H are prepared inaccordance with the procedures of Examples 14, 16 and 17.

EXAMPLE 49 4-(3,4-Dihydro-3-oxo-1,4[2H]-benzothiazin-6-yl)-4-oxobutyricacid

To 100 g of aluminum chloride was added 15.6 ml of dimethylformamide. Tothe hot slurry was added an intimate mixture of 17 g of3,4-dihydro-3-oxo-1,4[2H]-benzothiazine and 10 g of succinic anhydride.After 15 minutes at 75° C., the mixture was poured into 600 ml of iceand the precipitate collected by filtration and washed with water thenacetone to give 20 g (73% yield) of named compound decomposing at215°-218° C.

Theor. C₁₂ H₁₁ NO₄ S.1/2H₂ O: C, 52.54; H, 4.42; N, 5.11. Found: C,52.54; H, 4.20; N, 5.18.

The following compounds are prepared by the above procedure, using theappropriate starting materials:

4-(3,4-dihydro-2-methyl-3-oxo-1,4[2H]-benzothiazin-6-yl-oxobutyric acid,and

4-(3,4-dihydro-2,2-dimethyl-3-oxo-1,4[2H]-benzothiazin-6-yl-oxobutyricacid.

EXAMPLE 50 Methyl4-(3,4-dihydro-4-methyl-3-oxo-1,4[2H]-benzothiazin-6-yl)-4-oxobutyrate

4-(3,4-Dihydro-3-oxo-1,4[2H]-benzothiazin-6-yl)-4-oxobutyric acid (3 g)was suspended in 50 ml of dimethylformamide and 2.2 equivalents of 60%sodium hydride (1.0 g) were added. After 30 minutes at room temperature,2.2 equivalents of methyl iodide (3.5 g) were added and the mixturestirred overnight. The mixture was poured into ice water and theprecipitate collected by filtration. The solid was characterized by 1HNMR and used in the next reaction (see Example 54).

The following compounds are prepared by the above procedure, using theappropriate starting materials:

Methyl4-(3,4-dihydro-2-methyl-3-oxo-1,4[2H]-benzothiazin-6-yl-oxobutyrate, and

Methyl4-(3,4-dihydro-2,2-dimethyl-3-oxo-1,4[2H]-benzothiazin-6-yl-oxobutyrate.

EXAMPLE 514-(3,4-Dihydro-3-oxo-1,4[2H]-benzothiazin-7-yl)-3-methyl-4-oxobutyricacid

3,4-Dihydro-3-oxo-7-(1-oxopropyl)-1,4[2H]-benzothiazine (5.0 g) wasadded to a mixture of 2.25 ml of formalin solution and 2.72 g ofdimethylamine hydrochloride in 7.5 ml of acetic anhydride and heated to100° C. overnight. Acetone (20 ml) was added and the mixture heated atreflux for 15 minutes before the volitiles were removed at reducedpressure. The residue was taken up in 1N HCl and washed with ethylacetate. The aqueous portion was chilled in ice and basified with 12.5NNaOH. The basic solution was extracted with ethyl acetate and dried oversodium sulfate. The solvent was removed and the residue taken up inacetone and 3 ml of methyl iodide added. The mixture was heated atreflux for three hours, then cooled, and the precipitate collected byfiltration and washed with acetone to give 6.6 g of the quaternaryammonium salt of the mannich product.

The quaternary salt (6.6 g) was dissolved in 20% methanol/water and 3.8g of potassium cyanide in 30 ml of water was added. The mixture wasstirred at room temperature for 48 hours and the resultant precipitatecollected by suction filtration to give4-(3,4-dihydro-3-oxo-1,4[2H]-benzothiazin-7-yl)-3-methyl-4-oxobutyronitrile.The nitrile was heated to reflux in 200 ml of 6N HCl for 30 minutes,then cooled and diluted with an equal volume of ice water. The solidcollected was used in Example 55.

EXAMPLE 52 Methyl4-(3,4-dihydro-4-methyl-3-oxo-1,4[2H]-benzothiazin-7-yl)-3-methyl-4-oxobutyrate

4-(3,4-Dihydro-3-oxo-1,4[2H]-benzothiazin-7-yl)-3-methyl-4-oxobutyricacid (1.7 g) was dissolved in 50 ml of dimethylformamide and 0.23 g of60% sodium hydride was added. After 30 minutes, 0.7 ml of methyl iodidewas added and the mixture stirred at room temperature for three hours,then poured into 100 ml of ice water and extracted with ethyl acetate.The organic layer was washed with brine and dried over sodium sulfateand evaporated. The residue was chromatographed on a silica gel columneluted with 5% methanol in methylene chloride. The solvent was removedand the oil obtained was used in Example 56.

EXAMPLE 536-(3,4-Dihydro-3-oxo-1,4[2H]-benzothiazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-one

4-(3,4-Dihydro-3-oxo-1,4[2H]-benzothiazin-6-yl)-4-oxobutyric acid (2.0g) was suspended in 60 ml of ethanol and 1 ml of hydrazine added. Themixture was heated at reflux for three hours, then cooled slowly.Filtration gave 1.85 g of the title compound, mp 299°-302° C.

Theor. C₁₂ H₁₁ N₃ O₂ S.1/2H₂ O: C, 53.32; H, 4.48; N, 15.55. Found: C,53.02; H, 4.26; N, 15.94.

The following compounds are prepared by the above procedure, using theappropriate starting materials:

4-(3,4-dihydro-2-methyl-3-oxo-1,4[2H]-benzothiazin-6-yl-oxobutyric acid,and

4-(3,4-dihydro-2,2-dimethyl-3-oxo-1,4[2H]-benzothiazin-6-yl-oxobutyricacid.

EXAMPLE 546-(3,4-Dihydro-4-methyl-3-oxo-1,4[2H]-benzothiazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-one

Methyl4-(3,4-dihydro-4-methyl-3-oxo-1,4[2H]-benzothiazin-6-yl)-4-oxobutyrate(2.5 g) was heated at reflux in 70 ml of ethanol containing 1 ml ofhydrazine for three hours. Filtration gave 1.5 g of the named compound,melting at 241°-242° C.

Theor. C₁₃ H₁₃ N₃ O₂ S.1/4H₂ O: C, 55.80; H, 4.88; N, 15.02. Found: C,55.64; H, 4.87; N, 15.06.

The following compounds are prepared by the above procedure, using theappropriate starting materials:

4-(3,4-dihydro-2,4-dimethyl-3-oxo-1,4[2H]-benzothiazin-6-yl-oxobutyricacid, and

4-(3,4-dihydro-2,2,4-trimethyl-3-oxo-1,4[2H]-benzothiazin-6-yl-oxobutyricacid.

EXAMPLE 556-(3,4-Dihydro-3-oxo-1,4[2H]-benzothiazin-7-yl-2,3,4,5-tetrahydro-5-methylpyridazin-3-one

4-(3,4-Dihydro-3-oxo-1,4[2H]-benzothiazin-7-yl)-4-oxo-3-methylbutyricacid (1.2 g) was heated at reflux overnight in 50 ml of ethanolcontaining 0.2 ml of hydrazine. Filtration gave a white powder which waschromatographed on silica gel eluted with 5% methanol in methylenechloride, yielding 180 mg of the title compound melting >300° C.

Theor. C₁₃ H₁₃ N₃ O₂ S.1/4H₂ O: C, 55.80; H, 4.88; N, 15.02. Found: C,56.13; H, 4.75; N, 15.00.

EXAMPLE 566-(3,4-Dihydro-4-methyl-3-oxo-1,4[2H]-benzothiazin-7-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one

Methyl4-(3,4-dihydro-4-methyl-3-oxo-1,4[2H]-benzothiazin-7-yl)-4-oxo-3-methylbutyrate(1.7 g) was heated at reflux overnight with 0.3 ml of hydrazine in 50 mlof ethanol. Filtration gave a white powder which was chromatographed onsilica gel eluted with 5% methanol in methylene chloride, yielding 110mg of the named compound, mp 193°-194.5° C.

Theor. C₁₄ H₁₅ N₃ O₂ S: C, 58.10; H, 5.24; N, 14.52. Found: C, 57.81; H,5.42; N, 14.15.

EXAMPLE 57 3,4-Dihydro-3-oxo-6-oxopropyl-1,4[2H]benzothiazine

4-Amino-3-thiocyanatopropriophenone (prepared by the method of K. D.Luess and R. Pohloudek-Fabini in Arch. Pharm. 299(10), 878-884 (1966))(35 g) was heated to reflux in 250 ml of water containing 90 g of sodiumsulfide nonahydrate. The solution was cooled to room temperature and 60ml of acetic acid was added. The precipitate that formed was collectedand washed with water giving the mercapto compound.

4-Amino-3-mercaptopropiophenone was stirred in 200 ml of watercontaining 8.5 g of sodium hydroxide. The resultant mixture was filteredand 22 g of sodium chloroacetate added to the filtrate in 150 ml ofwater. After 30 minutes, 4 ml of acetic acid was added and the mixtureheated to reflux. After 10 minutes, heat was removed and the mixturestirred at room temperature overnight. The yellow precipitate wascollected by filtration and washed with water to give, after drying,18.5 g of benzothiazine melting at 215°-220° C.

4-(3,4-Dihydro-3-oxo-1,4[2H]benzothiazin-7-yl)-4-oxobutyric acid wasprepared by the same method as above. The starting material for thispreparation was 4-aminophenyl-4-oxobutyric acid which is described byThyes in J. Med. Chem. 26, 800 (1983). Thiocyanation was carried out bythe method of K. D. Luess and R. Pohloudek-Fabini in Arch. Pharm.299(10), 878-882 (1966).

EXAMPLE 58 Cardiotonic Activity

The cardiotonic activity of the compounds was determined in accordancewith the method of Alousi, A. A., et al., J. Cir. Res. 45, 666 (1979).Basically, adult mongrel dogs were anesthetized with sodiumpentobarbital and artificially respired. Arterial pressure was recordedvia a femoral artery and the pressure pulse used to trigger acardiotachometer for heart rate. Left ventricular pressure was measuredwith a Millar catheter and dP/dt was derived. Cardiac output wasdetermined by measuring ascending aortic blood flow with anelectromagnetic flow probe and myocardial contractile force was measuredwith a Walton Brodie strain gauge sutured to the right ventricle. LeadII EKG was also recorded. A standard does of dopamine was administeredto assess myocardial responsiveness. Test compounds were administered byi.v. infusion or bolus administration and the effects on cardiovascularparameters were determined. Dose-related effects of the test compound onBP, HR, dP/dt max., C.F. and C.O. were compared to pretreatment controlvalues and expressed as a percentage change. The results are shown inTable I.

EXAMPLE 59 Phosphodiesterase Inhibitory Activity

The phosphodiesterase inhibitory activity was determined in accordancewith the method of Thompson, W. J. et al., in Adv. Cycli. NucleotideRes., Ed. Brooker, G. et al., Vol. 10, pp. 69-92 (1979). This assaymeasures the ability of compounds to inhibit cyclic nucleotidephosphodiesterase. This enzyme converts either cyclic AMP or cyclic GMPto the noncyclized AMP or GMP, respectively. Compounds were tested atvarious concentrations in the presence of cyclic AMP (0.10-1.0 μMcontaining 0.2 μCi ³ H-cyclic AMP), enzyme, and 0.05M Tris-Cl buffer (pH7.4, containing 5 mM MgCl₂). After a specified time, the reaction wasstopped by heating to 100° C. for one minute. After cooling, 0.10 ml ofa solution containing snake venom (1 mg/ml) was added and the reactionwas allowed to proceed for 30 minutes. Termination of this reaction wasaccomplished by the addition of 1.0 ml of 33% Dowex slurry to separatethe product from unconverted substrate. An aliquot was removed from thesupernatant and quantitated by liquid scintillation spectrometry. Theresults are shown in Table I as the IC₅₀ which is the concentration (μM)of compound required to inhibit 50% of the cyclic nucleotidephosphodiesterase activity.

                  TABLE 1                                                         ______________________________________                                        Compound                                                                      (Example) Dose (mpk).sup.a                                                                              CF.sup.b                                                                             IC.sub.50.sup.c                              ______________________________________                                         8        1.87            98       9.5                                         9        1.87            62     100                                          10        1.87            18     50                                           11        1.87            41     N.T..sup.d                                   12        1.87            92     50                                           13        1.87            71     100                                          14        1.87            30     80                                           15        1.87            125     8                                           16        1.87            173    30                                           17        1.87            62      4                                           18        0.47            50      8                                           19        0.47            98     40                                           20        1.87            71     630                                          21        0.47            74     18                                           22        0.47            136     2                                           23        0.47            134     8                                           24        0.47            54     14                                           25        0.47            31     13                                           26        0.47            156     5                                           27        0.47            117     6                                           28        0.47            46     15                                           29        0.47            12     56                                           30        0.47            124    20                                           31        0.47            33     38                                           33        0.47             8     30                                           36        0.47            40     24                                           37        0.47             4      8                                           38        0.47            24     31                                           39        0.47            18     28                                           40        0.47            22     26                                           41        0.47            60      7                                           42        0.47            15     100                                          43        0.47            104    35                                           46         0.075          130      0.3                                        47         0.075          109       0.3                                       53         0.075          21     25                                           54         0.075          11     22                                           55         0.035          160     <0.1                                        56         0.027          32      <0.1                                        ______________________________________                                         .sup.a I.V. dose used for cardiotonic activity assay.                         .sup.b Percent increase in cardiac force.                                     .sup.c Micromolar concentration for 50% inhibition of cyclic nucleotide       activity.                                                                     .sup.d Not tested.                                                       

What is claimed is:
 1. A compound of the formula ##STR11## where R₁, R₃,R₅ and R₆ are independently H, C₁₋₆ straight- or branched-chain alkyl orC-₃₋₆ cycloalkyl;Y is S or O; X is H₂ or O; and M is --CN or mono- ordi-C₁₋₆ alkyl amino; and the quaternary ammonium salts thereof providedthat when M is mono- or di-C₁₋₆ alkyl amino the substituent is attachedto the benzoxazine moiety at the 7-position.
 2. A compound of theformula ##STR12## where X is H₂ or O;Y is O or S; R₃ is H, C₁₋₆straight- or branched-chain alkyl or C₃₋₆ cycloalkyl, and when X is H₂,R₃ is also C₂₋₆ acyl, arylacyl or C₁₋₆ alkylsulfonyl; R₅ and R₆ areindependently H, C₁₋₆ straight- or branched-chain alkyl or C₃₋₆cycloalkyl; R, W and Z are independently H, C₁₋₆ straight- orbranched-chain alkyl, C₂₋₆ acyl or --C(O)CHR₄ CH₂ C(O)OR₇ provided thatone of R, W and Z is --C(O)CHR₄ CH₂ C(O)OR₇ ; R₄ is H, C₁₋₆straight-branched-chain alkyl or C₃₋₆ cycloalkyl; and R₇ is H or C₁₋₆straight- or branched-chain alkyl; provided that when one of R, W and Zis --C(O)CHR₄ CH₂ C(O)OR₇ then the other cannot be --C(O)CH₄ CH₂ C(O)OR₇and R, W or Z is not --C(O)CHR₄ CH₂ C(O)OR₇ in the 6 position.
 3. Acompound of the formula ##STR13## where R₁, R₃, R₅ and R₆ areindependently H, C₁₋₆ straight- or branched-chained alkyl or C₃₋₆cycloalkyl; andR₇ is H or C₁₋₆ straight- or branched-chain alkyl.
 4. Thecompound of claim 3 which is4-oxo-4-(3,4-dihydro-3-oxo-1,4(2H)-benzoxazin-7-yl)-3-methylbutyricacid.
 5. The compound of claim 3 which is methyl4-oxo-4-(3,4-dihydro-4-methyl-3-oxo-1,4(2H)-benzoxazin-7-yl)-3-methylbutyrate.6. The compound of claim 1 which is4-oxo-4-(3,4-dihydro-3-oxo-1,4(2H)-benzoxazin-7-yl)-3-methylbutyronitrile.7. The compound of claim 1 which is[3-oxo-3-(3,4-dihydro-4-methyl-3-oxo-1,4(2H)-benzoxazin-7-yl)-2-methylpropyl]trimethylammoniumiodide.
 8. The compound of claim 1 which is[3-oxo-3-(3,4-dihydro-4-methyl-3-oxo-1,4(2H)-benzoxazin-7-yl)-2-methylpropyl]dimethylamine.